Optionally alpha-substituted 1-amino-2,3, or 4-(cyclohexyl/- phenyl) methylpiperidines and precursors



United States Patent 3,128,276 OPTIONALLY OL-SUBSTITUTED 1-AMINO-2,3, OR

4 (CYCLOHEXYL/ PHENYL)METHYLPIPERI- DINES AND PRECURSORS Kurt J. Rorig,Glenview, Ill., assignor to G. D. Searle & Co., Chicago, Ill., acorporation of Delaware No Drawing. Filed Sept. 9, 1960, Ser. No. 54,8625 Claims. (Cl. 260-293) This invention relates to cyclic hydrazinescomprising a piperidine nucleus substituted on the nitrogen atom by anamino radical and on one of the carbon atoms by a carbocyclic radicalattached via an optionally substituted methylene bridge. Moreparticularly, this invention elates to cyclic hydrazines of the formula+-Carbo N R %-Carbo wherein Carbo, R, and Z have the meanings previouslyset forth; Q is selected from among hydrogen and lower alkyl,hydroxy(lower alkyl), and lower alkenyl radicals, as also such aralkylradicals as benzyl, phenethyl, and naphthylmethyl; X is one equivalentof an anion-for example, chloride, bromide, iodide, nitrate, phosphate,sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate,toluenesulfonate, acetate, lactate, succinate, malate, maleate,tartrate, citrate, gluconate, ascorbate, benzoate, cinnamate, or thelike-which, in combination with the cationic portion of a saltaforesaid, is neither pharmacologically nor otherwise undesirable inphysiological dosage; and n is a positive integer less than 3.

The compounds to which this invention relates are use ful because oftheir valuable pharmacological properties.

Thus, for example, they are antibiotic and anti-fungal agents effectiveagainst B. subtilis, E. coli, T richophyton mentagrophytes, and likeorganisms, and they also affect the central nervous system. Theirantibiotic activity is the more remarkable because of the absence ofthis utility in compounds lacking the hydrazine function but otherwisesuperficially related. Such compounds as 1-(2- diethylaminoethyl)-a,u-diphenyl-4-piperidinemethanol and1-(2-diethylaminoethyl)-u,a-diphenyl2 piperidinemethanol, products ofapplicants copending application Serial No. 813,339, filed May 15, 1959,are without effect on B. subtilis and E. coli in standardized tests forantibiotic response, whereas the corresponding hydrazines hereindisclosed and claimed, illustratively =1-amino-a,u-diphenyl2-piperidinemethanol, significantly inhibit the growth of theseorganisms under identical conditions of test.

Manufacture of the subject compositions proceeds by lithium aluminumhydride reduction of the l-nitroso precursors lTIO I O-Carbo in an inertethereal solvent medium, temperatures being most desirably maintainedbelow 35 C. for reaction times ordinarily upwards of 2 hours. Carbo, R,and Z in the formula for the precursors have the same meanings assignedbefore. Conversion of the free bases of this invention to correspondingacid addition salts is accomplished by simple admixture thereof with 1or 2 equivalents of any of various inorganic or strong organic acids,the anionic portion of which conforms to X as hereinabove defined. Thequaternary ammonium compounds comprehended are those derived bycontacting a claimed base with an organic ester of the formula Q and Xbeing limited by the meanings previously assigned. Either I or 2 QXaggregates may be incorporated, quaternization taking place in thetemperature range between 25l00 C. in the presence of an inert solventsuch as chloroform, acetone, butanone, methanol, butanol, or the like.Quaternization is ordinarily completed in from 1 to 48 hours and isgenerally carried out in a closed system if a lower alkyl halide-such asmethyl chlorideis one of the reagents. Using methyl bromide. themanufacture of quaternary salts may be smoothly effected in butanonesolution at 70 C., the reaction time being approximately 1 hour.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirmanufacture. However, the invention is not to be construed as limitedthereby, either in spirit or in scope, since it will be apparent tothose skilled in the art of organic synthesis that many modifications,both of materials and of methods, may be practiced without departingfrom the purpose and intent of this disclosure. Throughout the exampleshereinafter set forth, temperatures are given in degrees centigrade,pressures in millimeters of mercury, and relative amounts of materialsin parts by weight, except as otherwise noted.

EXAMPLE 1 (A) Z-benzyl-I-nitr0s0piperidine.-To a solution of 350 partsof ZabenZylpiperidine and 242 parts of 36% hydrochloric acid in 2000parts of water at is added, with agitation during 2 hours, a solution of144 parts of sodium nitrite in 1000 parts of Walter. Agitation at 75 iscontinued for 2 hours after the addition is completed, whereupon thepale yellow oil thrown down is extracted with ether. The ether extractis dried over anhydrous sodium :sulfate and stripped of solvent bydistillation. The re "due is 24benzyl-l-nituosopiperidine.

1(B) 1-amin0-2-benzylpiperidine.-'Ilo a solution of 98 parts of lithiumaluminum hydride in 2230 parts of anhydrous ether at the :boiling pointunder reflux is added, with agitation during 1 /2 hours, a solution of380 parts of 2-benzyl-l-nitrosopiperidine in 2840 parts of anhydrousether. Agitation at the boiling point under reflux is continued for 1hour atfiter the addition is completed, whereupon the suspension whichresults is cooled at 0-5 during decompositionof the organometalliccomplex formed in process by addition, seriatirn, of 103 parts of water,parts of aqueous 20% sodium hydroxide, and 361 parts of water. The whitegranular precipitate which appears is removed by filtration, and thefiltrate is stripped of solvent by distillation. The slightly yellowoily residue "a a3 is the desired 1-amino-Z-benzylpiperidine. Theproduct has the ilormula EXAMPLE 2 (A) 2-(cyclohexylmethyl)piperidine.Asolution of 100 parts of Z-benZylpyridine in 720 parts of ethanol inwhich is suspended 1 part of ruthenium dioxide is maintained withagitation at 100 under hydrogen at a pressure of 800 pounds per squareinch until hydro-gen uptake ceases. The resultant mixture is filtered,and the filtrate is stripped of solvent by vacuum distillation. Theresidue, at iwatenwhite oil, upon vacuum distillation a-ffords2-(cyclohexylmethyl)piperidine, boiling at 88- 94/2 mm. pressure. Theproduct solidifies on standing and melts at 3842.

(B) 2-(cyclohexylmethyl)piperidine hydrochloride.- From an ethanolicsolution of the base of the foregoing Part A of this example, uponacidification With e thanolic hydrogen chloride and subsequent dilutionwith anhydrous ether, there precipitates Z-(cyclohexylmethyl)piperidinehydrochloride, which melts at 208-2095".

(C) 2 cyclohexylmethyl-I-rzizrs0piperidine.S11bstitution of 362 parts of2-(cyclohexylmethyl)piperidine for the 350 parts of Z-benzylpiperidinecalled for in Example 1(A) afiords, by the procedure there detailed,2-cyclohexylmethyl-jl-nitrosopiperidine, as a pale yellow oil.

(D) 1 amin0-2-(cyclohexylmethyl)piperidine.--To a solution of 150 partsof lithium aluminum hydride in 3500 parts of anhydrous ether is added,with agitation and at a rate just suflicient to induce gentle boilingunder reflux, a solution of 565 parts of 2-cyclohexylmethyl-1-nitrosopiperidine in 3500 pants of anhydrous ether. When the addition iscompleted (-representatively, after 2 hours), the reactants are heatedfor a further 2 hours at the boiling point under reflux, then cooled andfinally decomposed by the slow consecutive addition of 154 parts of.water, 141 parts of aqueous 20% sodium hydroxide, and 540 .parts ofWater. The resultant mixture is filtered to remove solid inorganics,then stripped of solvent by distillation at atmospheric pressures.Vacuum distillation or the residue afiords the desired 1-amino-2-(cyclohexylmethyl)piperidine, boiling in the range 85- 95 at 1.0 mm.pressure. The product has the formula (E) 1amino-Z-(cyclohexylmethyl)piperidine hydrochloride-To a solution ofparts of l-amino-Z- (cyclohexylmethyl)piperidine in 48 parts of absoluteethanol is added 3 parts of hydrogen chloride. The resultant solution iswarmed and diluted with 800 parts of anhydrous ether to precipitateivory blades of lamino-Z- (:cyclohexylmethyl)piperidine hydrochloride.The product, collected on a filter and dried in :air, melts at 141- 144.

EXAMPLE 3 (A) l-nitr0s0-a-phenyl-Z-piperidinem.ethan0l.--Substitution of380 parts of a-phenyl-2 piperidinernethanol for the 350 parts ofZ-benzylpiperidine called for in Example 1(A) affords, by the procedurethere detailed, l-nitrosoaphenyl-2-piperidinemethanol (B) 1amino-mphenyl-2-piperidinemethan0l.Substltu tion of 408 parts of1nitroso-aphenyl-Z-piperidinemethanol for the 380 parts ofZ-benzyl-l-nitrosopiperidine called for in Example 1(B) affords, by theprocedure there detailed, 1-amino-a-phenyI-Z-piperidinemethanol, of theformula N l U011- EXAMPLE 4 (A) 4-diphenylmethyl-1-nitrosopiperidine.-Toa suspension of 503 pair-ts of 4-( diphenylmethyl) -p iperidine in 2000parts of water is added, With vigorous agitation, 240 parts of 36%hydrochloric acid. The resultant mixture is heated to 75-80 andmaintained thereat with. agitation While a solution of 144 parts ofsodium nitrite in 1100 parts of water is added over a 45-minute period.Heating at approximately is continued for 1% hours after addition of thenitrite is completed, whereupon the reactants are cooled to roomtemperature and filtered. The solid product thus isolated is4-diphenylmethyl1- nitrosopiperidine, Which, upon recrystallization fromligroin, melts at approximately 162-163".

(B) 1 -amino-4 (diphenylmethyl)piperidine. Approximately 54 parts of4-diphenylmethyl-l-nitrosopiperidine is continuously extracted with thecondensate from a solution of 14 parts of lithium aluminum hydride in710 parts of anhydrous ether at the boiling point under reflux. After 24hours, the extraction is stopped and the ethereal solution is decomposedby adding 15 parts of water, 14 parts of aqueous 20% sodium hydroxide,and 52 parts of Water, in that order. Precipitated solids are removed byfiltration, and the filtrate is stripped of solvent by distillation. Theresidual viscous, pale-yellow oil is1-amino-4-(diphenylmethyl)piperidine, of the formula (C)1-amin0-4-(diphenylmethyl)piperidine hydrochloride.To a solution ofparts of 1-amino-4-(diphenylmetl1yl)piperidine in 560 parts of absoluteethanol is added 14 parts of hydrogen chloride followed by 1225 parts ofanhydrous ether. The 1-amino-4-(diphenylmethyl)piperidine hydrochlorideWhich precipitates, recovered on a filter and dried in air, melts atapproximately 262-263.

EXAMPLE 5 (A) a-Cyclohexyl-a-phenyl-4-pyridinemethanol hydrochloride-Toa solution of cyclohexylmagnesium chloride prepared from 32 parts ofchlorocyclohexane and approximately 7 parts of magnesium in 350 parts ofanhydrous ether at temperatures of the order of 5 is added a solution of27 parts of 4-benzoylpyridine in 490 parts of anhydrous ether. Theresultant mixture is heated at the boiling point under reflux for /2hour, then poured onto a mixture of 120 parts of concentratedhydrochloric acid and 500 parts of ice. The ot-cyclohexyl-a-phenyl-4-pyridinemethanol hydrochloride which precipitates is collected on afilter and dried in air.

(B) a-Cycl'ohexyl-a-phenyl-4-piperidinemethanol hydrochloride.Asuspension of parts of a-cyclohexyl-aphenyl-4-pyridinemethanolhydrochloride and 1 part of platinum oxide in approximately 100 parts ofethanol is maintained with agitation at approximately 25 in contact withhydrogen at 50 pounds per square inch pressure until hydrogen uptakeceases. The suspension is then filtered, and the filtrate is stripped ofsolvent by vacuum distillation. The residue is a-cyclohexyl-a-phenyl-4piperidinemethanol hydrochloride.

(C) a Cyclo hexyl 1 nitroso-u-phenyl-4-piperidinemethanol-To 31 parts ofot-cyclohexyl-a-phenyl-4-piperidinemethanol hydrochloride suspended in500 parts of water at approximately 75 is added, with vigorous agitationduring 2 hours, a solution of 8 parts of sodium nitrite in 70 parts ofwater. The resultant mixture is maintained at 75 with agitation for afurther 3 hours, whereupon it is cooled and extracted with ether. Theether extract, dried over calcium sulfate and stripped of solvent bydistillation, affords as the residue,a-cyclohexyl-1-nitroso-oc-phenyl-4-piperidinemethanol.

(D) 1-amino-a-cyclohexyl-a-phenyl-4-piperidinemethan0l.To a solution of7 parts of lithium aluminum hydride in 140 parts of anhydrous ether isadded, with agitation during approximately 1 hour, a solution of 26parts of u-cyclohexyl-1-nitroso-a-phenyl-4-piperidinemethanol in 490parts of anhydrous tetrahydrofuran. Upon completion of the addition, thereactants are heated at the boiling point under reflux for /2 hour, thencooled at 0-5 While the organometallic complex formed in process isdecomposed by the consecutive addition of 14 parts of water, 13 parts ofaqueous 20% sodium hydroxide, and 49 parts of water. The resultantmixture is filtered, and the filtrate is stripped of solvent by vacuumdistillation to obtain the desired 1-amino-a-cyclohexyl-a-phenyl-4-piperidinemethanol as the residue. The product has the formula EXAMPLE6 (A) 1-nifros0-on,ot-diphenyl-2-piperidinemefhan0l.-To a suspension of304 parts of equ-diphenyl-Z-piperidinemethanol hydrochloride in 1000parts of water is added, with vigorous agitation during 35 minutes attemperatures of the order of 75, a solution of 72 parts of sodiumnitrite in 500 parts of water. Agitation at 75 is continued for 2 hourslonger, whereupon the reactants are cooled to room temperature andfiltered. The solid product thus isolated is1-nitroso-a,a-diphenyl-2-piperidinemethanol which, recrystallized fromethanol, melts at 178-180.

(B) 1-amino-a,a-diphenyI-Z-piperidinemethanol. To

a solution of parts of lithium aluminum hydride in 1400 parts of etheris added, with agitation at 2025 during 45 minutes, a solution of 254parts of l-nitrosoa,a-dipheny1-2-piperidinemethanol in 3100 parts oftetrahydrofuran. The resultant mixture is heated to the boiling pointand maintained thereat under reflux for 45 minutes, whereupon it ischilled to 05 and then decomposed by the sequential slow addition of 139parts of water, 127 parts of aqueous 20% sodium hydroxide, and 487 partsof Water. Precipitated solids are filtered off and extracted withapproximately 9000 parts of boiling tetrahydrofuran, and this extract isadded back to the filtrate. The combined filtrate and extract isstripped of solvent by vacuum distillation. The residue, recrystallizedfrom benzene, melts at 223-226. This material isl-aminoa,a-diphenyl-2-piperidinemethanol, of the formula What is claimedis: 1. A compound of the formula ltll-carb 2 wherein Carb represents amember of the class consisting of carbocyclic radicals having theformulas represents a member of the class consisting of hydrogen and aradical having the formula 1-amino-2-benzylpiperidine.

. l-amino-2-(cyclohexylmethyl)piperidine.

. 1-amino-4-(diphenylmethyl)piperidine.

. 1-amino-a,a-diphenyl-Z-piperidinemethanol.

References Cited in the file of this patent Braun et al.: DeutscheChemische Gesellschaft (Berichte), vol. 64 B, page 1872 (1872) Hanna etal.: Journal of the American Chemical Society, vol. 74, 3693 and 3694(1952).

1. A COMPOUND OF THE FORMULA
 2. 1-AMINO-2-BENZYLPIPERIDINE. 